Quiescent neural stem cells exit dormancy upon alteration of GABAAR signaling following radiation damage

Quiescent neural stem cells (NSCs) are considered the reservoir for adult neurogenesis, generating new neurons throughout life. Until now, their isolation has not been reported, which has hampered studies of their regulatory mechanisms. We sorted by FACS quiescent NSCs and their progeny from the subventricular zone (SVZ) of adult mice according to the \expression of the NSC marker LeX/CD15, the EGF receptor (EGFR) and the CD24 in combination with the vital DNA marker Hoechst 33342. Characterization of sorted cells showed that the LeX(bright)/EGFR-negative population was enriched in quiescent cells having an NSC phenotype. In contrast to proliferating NSCs and progenitors, the LeX(bright)/EGFR-negative cells, i.e. quiescent NSCs, resisted to a moderate dose of gamma-radiation (4 Gy), entered the cell cycle two days after irradiation prior to EGFR acquisition and ultimately repopulated the SVZ. We further show that the GABA(A)R signaling regulates their cell cycle entry by using specific GABA(A)R agonists/antagonists and that the radiation-induced depletion of neuroblasts, the major GABA source, provoked their proliferation in the irradiated SVZ. Our study demonstrates that quiescent NSCs are specifically enriched in the LeX(bright)/EGFR-negative population, and identifies the GABA(A)R signaling as a regulator of the SVZ niche size by modulating the quiescence of NSCs. (C) 2013 Elsevier B.V. All rights reserved.